IL-17 (IL-17A) is the signature cytokine of a relatively new CD4+ T helper subset, known as Th17 cells. IL-17 and Th17 cells are elevated in psoriasis, RA, SLE and other autoimmune diseases. Accordingly, Th17 cells have emerged as a major contributor to autoimmune pathology, which has translated into exciting avenues of therapeutic intervention. Most notably, antibodies against IL-17 or its receptor have shown promise in clinical trials for psoriasis and rheumatoid arthritis (RA), and are being evaluated in other conditions as well. Conversely, IL-17 is an essential mediator of immunity to extracellular microbes. Recent work has especially implicated IL-17 in immunity to fungi such as Candida albicans. IL-17 also plays a role in responses to commensal microbiota, where aberrant activity promotes systemic inflammation. Signals from intestinal flora contribute to immune homeostasis but also to autoimmunity, which are interconnected through the Th17/IL-17 axis. Although much research effort has focused on Th17 generation and function, the mechanisms by which IL-17 mediates downstream signals have received far less attention. The IL-17 receptor belongs to a unique cytokine receptor family that employs novel mechanisms of signaling. An emerging theme is that there are numerous mechanisms in place to constrain IL-17 and Th17 activity, and defects in these negative regulatory pathways contribute to autoimmunity and immunopathology. The first funding period of this grant focused on structure-function relationships in IL-17R with respect to downstream signal transduction pathways. In work during the first grant cycle, we identified 2 new signaling inhibitors never previously connected to the IL-17 pathway. One is a deubiquitinating enzyme that appears to target the NF-kappaB pathway. The other is a more poorly-understood signaling intermediate with multiple activities. Knockouts of either lead to uncontrolled systemic inflammation, mediated in part by signals from intestinal microbiota. We hypothesize that unrestrained IL-17 signaling also contributes to the underlying inflammation. The goal of this application is to understand in detail how IL-17 receptor signaling is inhibited, and the biological consequences of its inhibition, both with respect to baseline inflammation but also immunity to Candida albicans. These findings will ultimately provide information that may be used to enhance, predict, diagnose and/or treat IL-17-mediated inflammation.